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An original methodology using Digital Image Correlation (DIC) has been designed to precisely measure full-field shrinkages of injection molded polymer plates and then to give the opportunity to compare quantitatively extensive numerical simulations to experiments. The principle of the methodology is based on the full-field strain determination between a reference image of the mold and that of injection-molded parts, which are 275 × 100 × 2.2 mm3 plates. To allow for DIC calculation, 50 µm-depth engravings were machined by electro-discharge process at the surface of the mold. The result of the analysis is a 2D full-field shrinkage map over the whole plate surface (i.e. flow and transverse), with a standard deviation of 0.03%. The marking density has been shown to have a roughly linear influence on the precision of shrinkage measurement. This methodology allows the quantification of the effect of several injection parameters on in-plane shrinkage fields: holding pressure, injection flow rate and direction, geometry of injection gates, or geometrical constraints. Once the best set of parameters of material constitutive laws is identified for the simulation of polymer plates, the simulation procedure is ready to be applied on more complex 3D geometries.

BackgroundEnvironmental health promotion interventions may reduce endocrine disruptor (ED) exposure. PREVED (PREgnancy, preVention, Endocrine Disruptors) project was developed to improve knowledge, to enhance risk perception and to change exposure behavior. Our objective was to present the phases of PREVED project using the RE-AIM method.MethodsPREVED intervention consisted of 3 workshops during pregnancy. Reach, adoption, and implementation phases were assessed with qualitative studies. Efficacy study consisted of a three-arm randomized controlled trial (RCT) on 268 pregnant women: i) control group (leaflet) ii) intervention group in neutral location iii) intervention group in contextualized location. The main outcome was the percentage evolution of participants who reported consuming canned food. Secondary outcomes were evolution of psycho-social scores, evolution of ED presence in urine and ED presence in colostrum. ResultsThe intervention adoption was centered on upper-privileged women, but implementation assessment showed that key features (highly practical intervention) seemed to be carried out and had initiated some behavior changes. A total of 268 pregnant women participated in the intervention and 230 on randomized controlled trial (control group: 86 and intervention groups: 172). We found no significant differences in consumption of canned food and in percentage of women having a decrease of bisphenol A or parabens in urine, but we found significant increase in the evolution of risk perception score and overall psychosocial score in intervention groups (respectively: +15.73 control versus +21.03 intervention, p=0.003 and +12.39 versus +16.20, p=0.02). We found a significant difference in percentage of women with butylparaben detection between control group and intervention groups (13% versus 3%, p=0.03). ConclusionPREVED intervention is the first intervention research dedicated to perinatal environmental health education in France. By sharing know-how/experience in a positive non-alarmist approach, it improved risk perception, which is a key to behavior change aiming to reduce perinatal ED exposure. Including women in precarious situations stay a major issue.Trial registration number: Retrospectively registered on 31 July 2017 (when the first participant was enrolled in this non-drug intervention, ClinicalTrials.gov was centered in therapeutic trials): NCT03233984 - URL: https://clinicaltrials.gov/ct2/show/NCT03233984

Introduction: The digitalized PREVED (PREgnancy, PreVention, Endocrine Disruptor) questionnaire was used in the clinical practices of health professionals (HP) who adhered to the MEDPREVED strategy. The objectives were to assess the strategy and to determine if it could improve access to endocrine disruptor (ED) exposure prevention. Methods: After having filled in the digital questionnaire in HP waiting rooms, patients were invited to talk about ED exposure during the consultation. HPs were previously trained in ED and had received a prevention kit for their patients. After the seven-month implementation phase, the evaluation phase consisted of five mixed assessments: interviews with: (i) patients who were young children’s parents; (ii) patients in the general population; (iii) paediatricians; (iv) midwives; and a quantitative study on GPs. Assessment concerned feasibility, accessibility, and usefulness of the strategy; we then used the Levesque model to evaluate how it could improve access to ED exposure prevention. Results: The study included 69 participants. The strategy appeared feasible for the filling-out step due to digital and environment access. However, it depended on patient and HP profiles. The strategy seemed useful insofar as it facilitated reflexive investment, an intention to healthy behaviour and, rather rarely, talk about ED exposure. The beginning of this discussion depended on time, prioritizing of the topic and HP profile. The strategy has confirmed the Levesque model’s limiting factors and levers to access ED prevention. Conclusions: The MEDPREVED strategy is feasible, accessible, and useful in clinical prevention practice. Further study is needed to measure the impact on knowledge, risk perception and behavior of beneficiaries of the MEDPREVED strategy in the medium and long term.

Chlorinated derivatives of bisphenol A (ClxBPA) are endocrine disruptors that have seldom been studied. The aim was to assess the determinants of ClxBPA presence and bisphenol A (BPA) concentration in colostrum fluid. Pregnant women participating in the EDDS cohort study (France, 2011–2014) received two visits at home during their pregnancies, the objectives being to inform ourselves on their sociodemographic characteristics and consumption habits and to collect their urine samples. A colostrum sample was collected at delivery. All samples were analyzed using solid-phase extraction coupled with ultra-high-performance liquid chromatography isotope dilution tandem mass spectrometry method. Among 100 pregnant women, 32% had at least one ClxBPA detected in their colostrum fluid, 19% monochlorobisphenol-A, 23% dichlorobisphenol-A, 16% trichlorobisphenol-A and 2% tetrachlorobisphenol-A. After adjustment for sociodemographic factors, sample collection between 24 and 48 h after delivery was associated with lower ClxBPA presence in colostrum (OR = 0.06, 95%CI (0.01, 0.66) compared to colostrum collected during the first 24 h. BPA was detected in 60 colostrum fluids (61%) with mean concentrations of 2.1 ± 6.9 ng/mL. After adjustment, BPA was higher among women currently smoking during the third trimester (β = 1.20 95%CI (0.30, 2.09)) and lower when the sample was collected between 24 and 48 h after delivery (β = -0.72 95%CI (-1.43, -0.02)) compared to colostrum collection during the first 24 h after delivery. Sociodemographic factors, water exposure and food consumption were not associated with presence of ClxBPA in colostrum and concentration of BPA. Confirmation of these results with further powerful studies are needed, particularly those on kinetic investigation of ClxBPA excretion in colostrum would be interesting to improve storage condition’s knowledge.

Background Nowadays, the main challenge of transplantation is the improvement of long-term care, aiming at reducing treatment-related complications and at decreasing rejection rates. Patients’ adherence to both treatment and hygienic-dietary measures is mandatory to achieve these objectives. Adherence to immunosuppressive drugs is estimated to be only 70%. We hypothesized that the implementation of a personalized pharmaceutical plan (PPP) would increase adherence and therefore graft survival. Methods/design This study is a stepped-wedge cluster randomized trial with transplantation units defining clusters. Twelve clusters from 10 university hospitals were recruited. All centres started on the same day in the control phase. Every 7 weeks, one centre will switch to the intervention phase and remain there until the end of inclusions. We plan to recruit 1716 kidney and/or liver transplant patients. The intervention phase consists in setting up the PPP: development of the patient’s hospital and community pharmaceutical follow-up. In the hospital, the pharmacist will carry out drug reconciliation upon admission, daily pharmaceutical follow-up of prescriptions and pharmaceutical interviews with the patient in order to explain the modalities of taking immunosuppressive drugs and hygienic-dietary measures. After hospitalization, during the post-transplantation year, pharmaceutical meetings will take place, prior to medical consultations in order to check the patient’s understanding of the prescription, his adherence, to remind them of hygienic-dietary measures and to look for adverse effects. The hospital pharmacist will also be in charge of establishing a close link with the community pharmacist (CP) and general practitioner, especially providing discharge medication reconciliation, an e-learning and a checklist. Moreover, prior to each pharmaceutical consultation, the hospital pharmacist will contact the CP to discuss patient adherence. The primary outcome is adherence to immunosuppressive treatments 1 year post-transplantation assessed by using the BAASIS questionnaire and the health insurance data from the national health data system. A medico-economic study will measure the efficiency of this plan. Discussion GRePH aims to increase adherence of liver and/or kidney transplant patients to their immunosuppressive therapies in order to reduce transplant rejections. To this end, a new clinical pharmacy model, the PPP, will be set up in 10 university hospitals. Trial registration ClinicalTrials.gov NCT04295928. Registered on 5 March 2020

Context Bisphenol A (BPA) is a ubiquitous contaminant with endocrine-disrupting effects in mammals. During chlorination treatment of drinking water, aqueous BPA can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or ClxBPA. Objective The aim of this study is to summarize and present the state of knowledge on human toxicological risk assessment of ClxBPA. Materials and Methods A search on ClxBPA in the PubMed database was performed based on studies published between 2002 and 2021. Forty-nine studies on chlorinated derivatives of BPA were found. Available information on their sources and levels of exposure, their effects, their possible mechanisms of action and their toxicokinetics data was extracted and presented. Results ClxBPA have been essentially detected in environmental aqueous media. There is evidence in toxicological and epidemiological studies that ClxBPA also have endocrine-disrupting capabilities. These emerging pollutants have been found in human urine, serum, breast milk, adipose and placental tissue and can constitute a risk to human health. However, in vitro and in vivo toxicokinetic data on ClxBPA are scarce and do not allow characterization of the disposition kinetics of these compounds. Conclusion More research to assess their health risks, specifically in vulnerable populations, is needed. Some water chlorination processes are particularly hazardous, and it is important to evaluate their chlorination by-products from a public health perspective.

The pediatric population suffers from a lack of age-appropriate medicines leading to unsafe situations when off-labelled or unlicensed drugs are used. Assessing the best option to administrate medicines when manipulations are required is essential in order to improve child care. This study aimed to compare the accuracy of the administered dose provided by three dosage forms and their techniques of administration. Different techniques of administration were assessed, covering three oral dosage forms (commercially available tablets, capsules, oral suspensions) using two APIs not available in a children-adapted dosage form. Techniques of administration were simulated and administered doses were determined using HPLC-UV. Means were compared to the target dose while distributions of doses were compared between each technique. For both APIs, mean administered doses obtained with capsules and tablets were significantly different from the target dose, whereas there was no statistical difference with oral suspensions. Distributions of doses showed significant difference between the three dosage forms. This study demonstrates that manipulations of solid oral dosage forms provide dramatic underdosing leading to unsafe situations. Compounded oral suspension is the best option to avoid underdosing and dose variation. This solution should be prioritized when age-appropriate commercial medicines are not available.

A positive association between Bisphenol A (BPA) exposure and coronary heart disease has been shown, but not in patients with type 2 diabetes (T2D). During the treatment of drinking water, chlorination leads to the formation of chlorinated derivatives of Bisphenol A (ClxBPA), that have higher estrogenic activity than BPA. No evidence exists for a relationship between exposure to ClxBPA and myocardial infarction in patients with T2D. The objective of this study was to evaluate the relationship between exposure to BPA, ClxBPA and the occurrence of myocardial infarction (MI) in patients with T2D. Two nested case-control studies in two independent European cohorts were performed. Each case with incident MI during follow-up was matched to one control on age, sex, and personal cardiovascular history in the same cohort. Association between baseline urine concentrations of BPA and of ClxBPA and incident MI was determined. Exposure to BPA was 31% in the ESTHER cohort and 18% in the SURDIAGENE cohort. In a meta-analysis of the two studies, occurrence of MI was significantly associated with urine BPA detection: adjusted OR = 1.97 (1.05-3.70), p = 0.04. Exposure to ClxBPA significantly differed in the SURDIAGENE and ESTHER studies: 24% and 8%, respectively (p = 0.0003). It was very strongly associated with MI in the SURDIAGENE cohort with an adjusted odds ratio (OR) of 14.15 (2.77-72.40) but this association was not replicated in the ESTHER study: adjusted OR: 0.17 (0.02-1.23). Whether these results may be explained by different water chlorination processes in France and Germany, resulting in different ClxBPA exposure levels, requires further investigation.

Background The suspected or actual effects on health of Endocrine Disrupting Chemicals (EDC) and their ubiquitous presence in everyday life justify the implementation of health promotion interventions. These interventions should ideally apply during critical windows like pregnancy. Perinatal environmental health education interventions may help to reduce EDC exposure during pregnancy. Methods/Design PREVED (Pregnancy, PreVention, Endocrine Disruptors) is an open-label randomized controlled trial assessing the impact of environmental health education intervention on EDC exposure during pregnancy. Inclusion, consent and randomization take place during the first trimester. The participants are randomly allocated into three groups: i) control group (information leaflet on EDCs), ii) intervention group in neutral location (information leaflet and workshops in a meeting room) and iii) intervention group in contextualized location (information leaflet and workshops in a real apartment). Workshops are organized between the second and third trimesters of pregnancy. Main outcome is the percentage of participants who reported consuming manufactured/industrial food. Secondary outcomes are: i) psycho-social dimensions ii) EDC concentrations in urine iii) EDC concentration in colostrum and iv) percentage of participants who reported consuming paraben-free personal care products. Discussion PREVED is a ground-breaking intervention research project dedicated to perinatal environmental health education that aims to identify pollutant sources in daily life and to offer accessible and realistic alternative solutions, by promoting the sharing of know-how and experience in a positive and non-alarmist approach. Trial registration number ClinicalTrials.gov: NCT03233984 (current status: ongoing). Retrospectively registered on 31 July 2017 (https://clinicaltrials.gov/ct2/show/NCT03233984) because when the first participant was enrolled in this non-drug intervention, ClinicalTrials.gov was centred in therapeutic trials. World Health Organization Trial Registration Data Set: Additional file 1

Active tobacco exposure during pregnancy is a known determinant of fetal growth. Nitrates and atrazine metabolites in drinking water may affect fetal growth as a mixture of endocrine disruptors (ED). We aimed to determine whether EDC have an additional effect on fetal growth compared to active tobacco exposure. A historic cohort study was carried out with a sample stratified with regard to the maternity unit, drinking water exposure, and year of birth. The women included were living in Deux-Sèvres, had given birth between 2005 and 2010 in three selected maternity units, and ultrasound data were available in their obstetrical records. Mixed linear models were used to analyze fetal weight evolution from the second trimester to the time of birth according to drinking water exposure to EDC mixture and active tobacco exposure. We included 558 mother-neonate couples, of whom 9% were exposed to high doses of the mixture and 21% to active tobacco smoking. There was no difference in fetal weight evolution according to drinking water mixture exposure (0.97 g, 95% CI [−3.01, 4.94]). We could not show a supplementary effect of mixture exposure in drinking-water on fetal growth as compared to active tobacco exposure. Further research is needed, using more precise methods to estimate EDC exposure.

This paper characterizes and analyzes the microstructures of injection-molded polypropylene parts reinforced with 20 wt% of hemp fibers in order to understand the process induced variations in thermomechanical properties. In-thickness fiber orientation and fiber content were determined by X-ray tomography along the flow. The fiber content along the flow path was also determined by direct fiber content measurements after matrix dissolution, showing an increase of 2%/100 mm for a 2.2 mm-thick plate due to fiber migration during the filling stage. A typical shell/core structure for fiber orientation in injection molding was observed, but with a very clear transition between the layer solidified under high shear rates and the core in which the fiber content was reduced by more than 50%. The orientation of hemp fibers is lower than the one of glass fibers, especially in thickness direction. However, the overall fiber orientation in the injection direction induces significant anisotropic thermomechanical properties, which cannot be explained by simple micromechanical models that consider isotropic mechanical properties for hemp fibers. These phenomena must be taken into account in process simulation codes for injection molding to better predict thermomechanical properties as well as part shrinkage and warpage to design molds. This paper characterizes and analyzes the microstructures of injection-molded polypropylene parts reinforced with 20 wt% of hemp fibers in order to understand the process induced variations in thermomechanical properties. In-thickness fiber orientation and fiber content were determined by X-ray tomography along the flow. The fiber content along the flow path was also determined by direct fiber content measurements after matrix dissolution, showing an increase of 2%/100 mm for a 2.2 mm-thick plate due to fiber migration during the filling stage. A typical shell/core structure for fiber orientation in injection molding was observed, but with a very clear transition between the layer solidified under high shear rates and the core in which the fiber content was reduced by more than 50%. The orientation of hemp fibers is lower than the one of glass fibers, especially in thickness direction. However, the overall fiber orientation in the injection direction induces significant anisotropic thermomechanical properties, which cannot be explained by simple micromechanical models that consider isotropic mechanical properties for hemp fibers. These phenomena must be taken into account in process simulation codes for injection molding to better predict thermomechanical properties as well as part shrinkage and warpage to design molds. This research was funded by the Association Nationale Recherche Technologie, France, based on the decision number 2017/1103 and Faurecia company.

International audience; In the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, hydroxychloroquine has been proposed as a potential agent to treat patients with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 infection. Older adults are more susceptible to COVID-19 and some patients may require admission to the intensive care unit, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, a liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and SyrSpend(Ⓡ) SF PH4 (dry) suspending vehicle. Moreover, a fully validated stability-indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3 °C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Resume Objectifs L’objectif de cette etude a ete de quantifier l’apport en parabenes du a l’administration des medicaments chez les nouveau-nes durant l’hospitalisation qui fait suite a leur naissance. Methodes Une etude monocentrique prospective a ete realisee dans un service de neonatalogie afin de recueillir l’ensemble des prescriptions. Une liste exhaustive des medicaments contenant des parabenes commercialises en France a ete repertoriee a partir de la base de donnees Theriaque. Cette liste a ete croisee avec les prescriptions recueillies afin d’etablir un profil d’exposition aux parabenes. Pour chaque medicament prescrit contenant des parabenes, un dosage par HPLC-UV a ete realisee afin de determiner la dose journaliere de parabenes moyenne recue par les nouveau-nes hospitalises. Resultats Plus de 300 specialites commercialisees en France contiennent au moins un parabene. Dans la majorite des cas, les medicaments contiennent une association de methylparabene et de propylparabene. Tous les nouveau-nes hospitalises (n = 22) ont ete exposes au moins une fois au methylparabene et au propylparabene via les medicaments tandis que 50 % ont ete exposes au propylparabene. La dose journaliere moyenne recue etait plus importante chez les nouveau-nes a terme (572,0 ± 249,0 versus 414,6 ± 294,1 μg/kg/j pour le methylparabene) mais la frequence d’exposition etaient plus importantes chez les nouveau-nes prematures (65,0 versus 78,6 % pour le methylparabene) ainsi que les doses cumulees (1421,5 ± 758,8 versus 8618,7 ± 7922,3). Ces doses sont inferieures aux valeurs toxicologiques de reference mais ces dernieres ne prennent pas en compte l’effet perturbateur endocrinien de ces composes. Conclusions Ces resultats demontrent que les medicaments sont une source importante d’exposition aux parabenes chez les nouveau-nes hospitalises apres leur naissance. Ces resultats doivent inciter les industriels et les professionnels de sante a privilegier des prises en charge therapeutiques sans parabenes.

Highlights • Hydroxychloroquine has been proposed as a potential agent to treat COVID-19 patients • Oral drug administration of solid forms may be comprised in many patients • Liquid formulation of hydroxychloroquine is not commercially available • Compounded hydroxychloroquine oral suspension is stable over 60 days, In the context of the SARS-CoV-2 pandemic, hydroxychloroquine has been proposed as a potential agent to treat COVID-19 patients. Older adults are more susceptible to COVID-19 and some patients may require admission in intensive care units, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and Syrspend SF dry pH4® suspending vehicle. Moreover, a fully validated stability indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3°C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Bisphenol A (BPA) is a well-known ubiquitous chemical found in polycarbonate, polysulfone and epoxy resins, used in mass production for many consumer products. BPA exhibits endocrine disruptor properties that can potentially induce adverse health effects. In aquatic environments, it can react with chlorine to produce chlorinated derivatives (ClxBPAs). ClxBPAs exhibit oestrogenic activity 10 to 105 times higher than BPA itself. Assessing human exposure to endocrine disrupting chemicals is mandatory to assess health risk. Blood, as well as urine matrix, are commonly used to perform human biomonitoring. We therefore developed, fully validated and applied a method based on Ultra High Performance Liquid Chromatography couples to a Triple Quad Mass Spectrometer to determine BPA, monochlorobisphenol A (MCBPA), dichlorobisphenol A (DCBPA), trichlorobisphenol A (TCBPA) and tetrachlorobisphenol A (TTCBPA) in human blood plasma. The European Medicines Agency guidelines for bioanalytical method validation have been applied. Precision and trueness of the method were15% at medium and high levels of quality control and20% at the limits of quantification (LOQs). The LOQs were settled at 0.1 ng/mL for BPA, 0.02 ng/mL for TTCBPA and 0.005 ng/mL for MCBPA, DCBPA, and TCBPA. The analytical method was applied to ten patients suffering from end stage renal disease. BPA was quantified in all ten patients while MCBPA, DCBPA and TTCBPA were determined in three and TCBPA in four. In conclusion, we have successfully developed a highly sensitive method to determine BPA and ClxBPAs in human plasma. Thanks to this method, for the first time, we could demonstrate ClxBPAs occurrence in human blood.

Background Active tobacco exposure during pregnancy is known to be an important determinant of fetal growth. Nitrates and atrazine metabolites in drinking water may affect fetal growth as a mixture of endocrine disruptors (ED). Our aim was to determine whether ED have an additional effect on fetal growth compared to the known and observed effect of active tobacco exposure during pregnancy. Methods A historic cohort study was carried out with a sample stratified with regard to maternity ward, drinking water exposure and year of birth. The women included were living in Deux-Sèvres, had given birth between 2005 and 2010 in three selected maternity wards, and ultrasound data from pregnancy were available in their obstetrical records. Mixed linear models were used to analyze fetal weight evolution from second trimester of pregnancy to time of birth according to drinking water exposure to atrazine metabolite and nitrate mixture and active tobacco exposure. Results We included 558 mother-neonate couples, of whom 8.5% were exposed to high doses of mixture and 20.5% to active tobacco smoking. There was no significant difference in fetal weight evolution according to drinking water mixture exposure (0.97 g; 95% CI [-3.01;4.94]) and when comparing nested models with and without drinking water mixture exposure, the likelihood ratio (LR) test was not significant (LR khi²=6.6, p=0.252). Conclusion We could not show a supplementary effect of mixture exposure on fetal growth as compared to active tobacco exposure. Further research is needed, using more precise methods to estimate ED exposure.

Introduction Les dosages biologiques sont tous soumis a une limite de quantification (LOQ) des methodes analytiques utilisees. Cela amene a analyser dans les etudes des variables contenant des donnees manquantes (DM) de facon non aleatoires (MNAR). Plusieurs dosages issus des memes echantillons peuvent etre a la fois correles entre eux et faire l’objet de DM liees a une limite de quantification. L’objectif du projet est de reussir a simuler ce type de DM afin d’etudier et de comparer les differentes techniques d’imputations simple et multiple proposees dans le cas de donnees manquantes MNAR. Methodes La cohorte EDDS (« Endocrine Disrupting Deux-Sevres »), visant a comparer des methodes d’estimation de l’exposition hydrique aux perturbateurs endocriniens chez des femmes enceintes, a donne lieu a la creation d’une base de donnees contenant cinq variables correlees avec des donnees manquantes MNAR. L’etude porte sur les differentes formes de Bisphenol A chlores pouvant se retrouver dans l’eau a destination de consommation humaine sous les formes mono, bi, tri ou tetrachlorees. Les dosages des cinq molecules montrent une LOQ atteinte dans au moins 35 % des echantillons et jusqu’a 88 % de donnees non quantifiables. Les differentes formes de la molecule cohabitent dans l’eau, leurs concentrations sont liees. La simulation des donnees d’etude est realisee a partir de l’exponentielle de plusieurs lois normales dont les parametres ont ete fixes a la suite de l’observation des differentes distributions des donnees de la cohorte EDDS. Des contraintes supplementaires ont ete ajoutees necessitant la creation de set de donnees par iterations jusqu’a obtenir cinq variables correlees ayant des taux de DM differents les uns des autres. Les methodes d’imputation comparees sur les donnees simulees sont l’imputation simple par la moitie de la valeur de LOQ (HM), les imputations multiples : QRILC, MICE, BLOQ, GSimp, et kNN-TN. Ces methodes sont comparees a l’aide de l’indicateur NRMSE. Resultats Les parametres de la simulation sont la creation d’une base de donnees de 100 dosages, contenant cinq variables continues avec un taux de DM respectivement de 30 %, 45 %, 60 %, 75 % et 90 %. La correlation de Spearman souhaitee entre les differentes variables est comprise entre [0,30 ; 0,85]. Chacune des cinq variables simulees a une moyenne et un ecart type specifiques et fixes, associes a l’exponentielle d’une loi normale. Ces parametres sont choisis afin de se rapprocher le plus possible des donnees de la cohorte EDDS. Cent sets de donnees sont construits. La mediane (Quartile1- Quartile3) des iterations necessaires a leur creation est de 2028 (902-3438) pour un temps median machine de 6,5 (2,8-10,8) secondes. Les differentes methodes d’imputation citees sont appliquees sur ces donnees. Les methodes HM et GSimp montrent la plus faible difference entre les donnees simulees et celles imputees. Leurs performances evaluees par NRMSE pour ces deux methodes d’imputation sont proches. Conclusion Les techniques iteratives permettent de simuler des variables correlees les unes aux autres en presence de donnees manquantes MNAR. Les methodes HM et GSimp semblent les plus performantes pour imputer des variables contenant ce type de donnees manquantes. La prise en compte de differentes LOQ au sein d’une meme variable, de variables d’ajustement et de tailles de jeux de simulations differentes sont les perspectives de travail de cette etude.

Les perturbateurs endocriniens (PE) sont des substances etrangeres a notre organisme, d’origine chimique ou naturelle, qui perturbent le fonctionnement du systeme endocrinien et induisent des pathologies telles que des troubles de la reproduction, de l’obesite, du diabete, le cancer du sein ou de la prostate,… Dans notre equipe Inserm, nous focalisons nos recherches sur les derives halogenes, chlores et/ou bromes, du Bisphenol A et des parabenes, formes lors de la derniere etape du traitement de l’eau du robinet avec du chlore, utilise comme antibacterien. Nous nous interessons a ces produits halogenes car il apparait dans la litterature que la majorite de ces derives possedent des effets endocriniens (estrogeniques, androgeniques,…) renforces par rapport aux molecules parents non chlores. Nous presenterons la synthese de ces composes halogenes du BPA, BPS et des parabenes qui servent de temoins analytiques dans l’analyse d’echantillons biologiques humains (sang, urine, colostrum,…), naturels (eau) ou afin d’evaluer leur profil toxicologique. Ainsi la preparation de plus d’une cinquantaine de ces composes a permis de nombreuses collaborations au niveau nationale et internationale. Un projet Anses, en cours, porte sur ces composes, l’evaluation de leur activite sur des recepteurs nucleaires et de leur tumorigenicite. Nous presenterons quelques etudes realisees sur la quantification par LC/MS-MS de ces composes chlores dans l’eau de boisson ou dans des matrices biologiques comme l’urine, le colostrum, la graisse. L’objectif de ces etudes est de quantifier l’exposition humaine face a ces substances et d’evaluer leurs proprietes reprotoxiques, de perturbateurs endocriniens.

BackgroundDexamethasone is commonly used to treat a wide variety of diseases including oncological disorders. The aim of this study was to propose a liquid formulation of dexamethasone. Therefore we have developed and assessed the stability of a 5 mg/mL dexamethasone oral suspension.MethodsA stability-indicating analytical method, using HPLC-UV, was developed and fully validated according to well-recognized international guidelines. The dexamethasone suspension was prepared using dexamethasone acetate powder and Ora-SweetResultsThe mean dexamethasone concentration of the compounded oral suspensions was equal to 5.07±0.17 mg/mL. No colour modifications, precipitate or suspending troubles was observed throughout the storage period and the pH of the oral suspensions was decreased slightly, from 4.41±0.01 to 4.20±0.02. According to the dexamethasone content determined by HPLC-UV, whatever storage condition was used, no significant degradation of dexamethasone occurred over the 60 days of the study period.ConclusionDexamethasone oral suspension prepared according to our conditions is stable over 60 days under regular storage temperatures (at 4±2 °C or at 21±3 °C).

Dexamethasone, hydrochlorothiazide, spironolactone, and phenytoin are commonly used in neonates, but no age-appropriate formulation containing these active pharmaceutical ingredients (APIs) is commercially available. Thus, pharmaceutical compounding of the liquid oral dosage form is required to enable newborn administration. A problem common to the compounded preparations described in the literature is that they include potentially harmful excipients (PHEs). Therefore, the aim of this study was to evaluate the feasibility of compounding oral liquid dosage forms free of PHE, containing dexamethasone, hydrochlorothiazide, phenytoin, or spironolactone and to assess their physicochemical stability. Due to the poor water solubility of the targeted APIs, oral suspensions were compounded using Syrspend&reg, SF-PH4 Dry, a suspending vehicle free of PHE. Four HPLC coupled to UV spectrometry (HPLC-UV) stability-indicating methods were developed and validated according to international guidelines to assay the strength of the targeted APIs. Whatever storage condition was used (5 &plusmn, 3 &deg, C or 22 &plusmn, 4 &deg, C), no significant degradation of API occurred in compounded oral suspensions. Overall, the results attest to the physical and chemical stability of the four oral liquid dosage forms over 60 days under regular storage temperatures. Finally, the use of the proposed oral suspensions provides a reliable solution to reduce the exposure of children to potentially harmful excipients.

Bisphenol A (BPA) and its chlorinated derivatives (Clx-BPA) are environmental pollutants exhibiting endocrine-disrupting (ED) properties suspected to be involved in the pathogenesis of hormone-dependent cancers, such as breast and prostate cancers. Due to their lipophilic properties, they may accumulate in adipose tissue which could therefore be a suitable matrix to assess long-term exposure to these compounds and relationships with the tumorigenesis of these cancers. An LC-MS/MS assay for the determination of BPA and Clx-BPA in adipose tissue samples was developed and fully validated according to current bioanalytical validation guidelines. Ionization was achieved using an electrospray source operating in the negative mode and quantification of target analytes was obtained in the multiple reaction monitoring mode. Both standard and quality control (QC) samples were prepared in blank adipose tissue samples. Linearity was demonstrated over the ranges 0.125 to 8.000 and 0.0125–0.8000 ng/mL for BPA and Clx-BPA, respectively. Accuracy and precision were demonstrated over the whole concentration range: intra and inter-day bias values were in the 85–114% range and imprecision of the method did not exceed 14%. Lower limits of quantification were validated using QCs at 0.1250 and 0.0125 ng/mL for BPA and Clx-BPA, respectively. Internal standard-corrected matrix effects were comparable in breast and prostate adipose tissues, demonstrating that this method could be used to reliably assay BPA and Clx-BPA in both tissues. The method was sensitive enough to determine BPA and Clx-BPA in breast adipose tissue obtained from women undergoing breast surgery, enabling identification of different patterns of exposure to these ED chemicals. The method enables the reliable quantification of BPA and Clx-BPA in adipose tissue and could be used to assess long-term exposure to these compounds and potential associations with hormone-dependent cancers.

Les perturbateurs endocriniens (PE) ont ete definis par l’Agence de Protection et de l’environnement des Etats Unis comme substance exogene qui alterent les fonctions du systeme endocrinien et induisent des effets nefastes sur la sante d’un organisme intact. Le Bisphenol A (BPA) est un PE qui interfere avec la synthese, metabolisme, transport, affinite des hormones naturelles. L’utilisation du BPA est tellement repandue dans l’environnement qu’il provoque de nombreux effets secondaires (cancers, anomalies du developpement, reprotoxicite, …). Le BPA est ubiquitaire, il est retrouve dans les sols, l’air et l’eau. Lors du traitement de l’eau du robinet, la derniere etape consiste a traiter avec du chlore afin d’eliminer des bacteries, cependant cette chloration mene egalement a la formation de derives chlores du BPA (ClxBPA). De plus la presence d’ions bromures dans l’eau, conduit a la formation de derives bromes du BPA (BrxBPA). Nous presenterons la synthese de ces composes ClxBPA, BrxBPA qui servent de temoins analytiques dans l’analyse d’echantillons biologiques humains ou afin d’evaluer leur toxicite. Une cohorte de femmes enceintes a permis de recueillir leur eau de boisson, des fluides biologiques (urine, colostrum) dont les analyses LC/MS-MS et GC/MS-MS seront detaillees sur leurs teneurs en derives halogenes du BPA. Enfin, les derives ClxBPA, BrxBPA ont ete evalues in vitro sur le recepteur Follitropine (FSHR). Ces composes ne sont pas cytotoxiques (test MTT), ils demontrent un effet allosterique negatif en presence de l’hormone FSH. Ces derives sont consideres comme des perturbateurs endocriniens et susceptibles d’avoir des effets reprotoxiques.

Bisphenol A (BPA) has been used in the plastics industry for several decades. During the treatment of drinking water with chlorine reagent, the formation of chlorinated derivatives of BPA (ClxBPA) but also bromoBPA and bromochloroBPA is to be expected. Some of these compounds are considered to have an estrogenic effect and could induce major risks for human health by targeting different organs and systems in the body. In this paper, we describe the synthesis of chloro- and bromobisphenol A (ClxBPA, BrxBPA, BrxClxBPA)and their analytical characterization. These derivatives could be used as analytical standards in LC-MS/MS or evaluated in in vitro biological tests for their potential as endocrine disruptors. In this study, we evaluated the presence of BPA, ClxBPA in a pilot study from water samples. Range values found for BPA, ClxBPA were respectively 2.8–4169.3 ng/L and 0.8–11.3 ng/L.

Introduction Dans l’optique de la reduction des couts, les recommandations du dernier rapport Morlat incitent a l’utilisation des generiques des traitements anti-retroviraux (ARV) actuellement disponibles pour le Truvada (TVD) et le Kivexa (KVX), notamment si le patient l’accepte, pouvant conduire au passage d’un traitement quotidien en un comprime par jour (STR) a un traitement en comprimes multiples (MTR). Nous avons voulu evaluer l’acceptabilite du passage aux generiques dans la vraie vie dans une cohorte de PVVIH. Materiels et methodes Entre le 01/11/2017 et 31/01/2018 tous les PVVIH traites efficacement (charge virale VIH Resultats Deux cent dix neuf patients ont ete inclus dans l’etude, repartis en 3 groupes : groupe 1 (n = 95) sous TVD ou KVX plus un 3e agent, groupe 2 (n = 82) sous un STR pouvant etre remplace par un MTR, groupe 3 (n = 42) avec une combinaison d’ARV sans passage au generique possible. L’âge moyen de la cohorte etait de 51,9 ans [25–87], sex-ratio 1,8. Le passage au generique dans le groupe 1 a ete realise pour tous les patients permettant de diminuer le cout annuel des ARV de 284 665 € (2996€/an/patient). Parmi les patients du groupe 2 (47 hommes et 35 femmes) d’âge moyen 50,3 ans [28–77], 48 % (n = 39) ont accepte de prendre un MTR (soit une economie annuelle de 97 586 € ou 2502 €/an/patient) ; parmi les autres, le maintien du STR a ete motive par la peur : de l’inobservance (n = 9), d’une intolerance (n = 2) et/ou d’un trop grand nombre de comprimes (n = 32). L’acceptation du passage d’un STR a un MTR etait liee au fait d’etre un homme (p Conclusion Les PVVIH ne s’opposent pas necessairement a la prescription de generiques, meme lorsqu’il s’agit de passer a un MTR, dans le but de reduire les couts de sante. Le passage vers les generiques a permis dans notre etude de reduire le cout annuel lie aux ARV de 382 251 euros. Dans la conjoncture actuelle, le patient doit etre implique a toutes les etapes de sa prise en charge et l’information concernant les generiques doit desormais s’inscrire pleinement a notre temps de consultation.

A few months ago, the pharmacy department of the University Hospital of Poitiers was located in the basement of the hospital; communicating with care units by fax, phone or messenger. Today, drugs and medical devices, are stored in a 3400m(2) logistic platform and most of the delivery activity is robotized. Control and validation of prescriptions and dispensing activities are done by the pharmaceutical teams directly in the care units. Quality indicators allow us to improve our services regularly. A great success and interesting prospects for clinical pharmacy.

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. We performed Monte Carlo simulations (MCS) to determine the best gentamicin pharmacokinetic profile (high peak and low trough concentrations). Then, 6 mg/kg of gentamicin was infused into 10 ICU patients over a period of 30 min. A 4-h-long hemodialysis session was started 30 min after the end of the infusion. Pharmacokinetic samples were regularly collected over 24 h. A one-compartment model with zero-order input and first-order elimination was developed in Nonmem version VI to analyze patients' measured gentamicin concentration-versus-time profiles. Finally, additional MCS were performed to compare the regimen chosen with the FDA-approved gentamicin regimen. High peak concentrations ( C max , 31.8 ± 16.8 mg/liter) were achieved. The estimated C 24 and C 48 values (concentrations 24 and 48 h, respectively, after the beginning of the infusion) were 4.1 ± 2.3 and 1.8 ± 1.2 mg/liter, respectively. The volume of distribution was 0.21 ± 0.06 liter/kg. MCS confirmed that the dosing regimen chosen achieved the target C max whereas the FDA-approved regimen did not (31.0 ± 10.9 versus 8.8 ± 3.1 mg · liter −1 ). Moreover, the C 24 values were similar while the AUC 0-24 values were moderately increased (190.8 ± 65.0 versus 135 ± 42.2 mg · h · liter −1 ). Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C max and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.

Background: The relationship between preterm birth (PTB) and endocrine disruptor exposure in drinking-water has only occasionally been studied. The objective of this work was to investigate the relation between exposure to atrazine metabolites, or atrazine/nitrate mixtures, in drinking-water during pregnancy and prevalence of PTB neonates, while taking neighborhood deprivation into account. Method: A historic cohort study in Deux-Sèvres, France, between 2005 and 2010 with a multiple imputation model for data of exposure to atrazine metabolites and a logistic regression were carried out. Results: We included 13,654 mother/neonate pairs living in 279 different census districts. The prevalence of PTB was 4%. Average atrazine metabolite concentration was 0.019 ± 0.009 (0.014–0.080) µg/L and 39% of mothers lived in less deprived areas. The individual data were associated with risk of PTB. The risk of PTB when exposed to highest concentration of atrazine metabolite adjusted for confounders, was ORa 1.625 95% CI [0.975; 2.710]. Taking, or not, neighborhood deprivation into account did not change the result. Exposure to atrazine/nitrate mixtures remained non-significant. Conclusions: Even if we took neighborhood deprivation into account, we could not show a significant relationship between exposure to atrazine metabolites, or mixtures, in drinking-water during the second trimester of pregnancy and PTB.